N-4-formyl-5-amino pyrazoles

ABSTRACT

A NOVEL SERIES OF N&#39;&#39;-(4-FORMYL)-5-AMIDO-PYRAZOLES WHICH ARE USEFUL AS INTERMEDIATS IN PREPARING N&#39;&#39;-(4(HYDROXYMETHYL)-5-PYRAZOLYL)AMIDINES, THE AMIDINES ARE EFFECTIVE ANTI-FLAMMATORY AGENTS.

Patented Aug. 22, 1972 3,686,171 N-4-FORMYL-5-AM1NO PYRAZOLES Leo RalphSwett and James Daniel Ratajczyk, Waukegan,

and Patrick Richard Young, Winthrop Harbor, 111., assignors to AbbottLaboratories, North Chicago, Ill. No Drawing. Continuation-impart ofapplication Ser. No. 672,717, Oct. 4, 1967, now Patent No. 3,544,585,dated Dec. 1, 1970. This application Dec. 2, 1970, Ser. No.

Int. Cl. C07d 49/20 US. Cl. 260-240 G 1 Claim ABSTRACT OF THE DISCLOSUREA novel series of N'-[4-formyl]-5- amido-pyrazoles which are useful asintermediates in preparing N-[4 (hydroxymethylJ-S-pyrazolyl]amidines.The amidine's are effective anti-inflammatory agents.

CROSS-REFERENCE TO RELATED APPLICATIONS This is a continuation-impart ofour co-pending application, Ser. No. 672,717 filed October 4, 1967, nowUS. Pat. 3,544,585 granted Dec. 1, 1970.

DESCRIPTION OF INVENTION This invention is directed to novelintermediates which are useful in preparing compounds having the generalstructural formula X" OHzOH N IF I R Y wherein A and W each representloweralkyl or, A and W together form a cyclic secondary amine, in thepresence of a suitable catalyst. This reaction yields a pyrazolederivative having the amide condense at the S-amino position and theformyl group substituted at the 4-position. This compound is thenreduced with any suitable reducing agent to yield the final product.

This reaction scheme may be represented as follows:

The reaction is carried out under heat and with an excess of theformylated secondary amine according to the Vilsmeier-Haack aldehydesynthesis reaction. The catalyst generally employed in this reaction isphosphorous oxychloride since this agent is unusually suited toaccomplish the condensation of the formyl group at the 4-position of thepyrazole ring. An excess amount of formylated secondary amine must beused since it supplies the formyl group for the 4-position condensationas well as supplying material for the condensation to the amine group atthe 5-position on the pyrazole ring. That is, the formylated secondaryamine supplies the carbon atom adjacent the double bond at the5-position nitrogen atom.

The formylated secondary amines suitable in the practice of thisinvention include the following: l-formylpiperidine, 1formyl-4-methylpiperazine, diethylformamide, l-forinylmorpholine anddimethylformamide. In the case where R is loweralkyl, other acylatedamines may be used. For example, N,N-dimethylacetamide in the presenceof phosphorous oxychloride condenses with the 1,3disubstituted-S-aminopyrazole to yieldN'-(1,3-disubstituted-S-pyrazolyl)N,N-dimethylacetamidine.

The 4-formyl group can then be introduced into the pyrazole nucleus bythe use of dimethylformamide and phosphorous oxychloride.

In order to better illustrate this invention, reference is made to thefollowing examples which are intended to describe several embodiments ofthe invention, and are not intended to limit same thereby.

EXAMPLE A Preparation of S-amino-1,3-diphenylpyrazole To a stirredsolution of 550 ml. of water and 150 ml. of concentrated hydrochloricacid, is added dropwise 108 grams (1.0 molar) of phenylhydrazine.Following this addition, 144 grams (1.0 molar) of 3-imino3-phenylpropionitrile is added and the reaction mixture is then heatedto -90 C. for 30 minutes. To the heated reaction mixture is slowly addedml. of concentrated hydrochloric acid and the mixture is heated toreflux for one hour. The mixture is then cooled in an ice bath and madealkaline by the addition of about 250 ml. of concentrated ammoniumhydroxide until a precipitate forms.

The precipitate is filtered and washed thoroughly with water, thendried. The product is crystallized from ethanol and water yielding 153grams of 5-amino-l,3-diphenylpyrazole having a melting point of 131-133C.

EXAMPLE B Preparation of S-amino-1-methy1-3-phenylpyrazole A mixture of13 grams (0.09 mole) of benzoylacetonitrile and 4.1 grams (0.09) mole)of methylhydrazine is refluxed together in 75 ml. of ethanol for 3hours. The solvent is then removed in vacuo and the residual oilcrystallized from ethyl acetate and a solvent consisting of a mixture ofsaturated hydrocarbons consisting mainly of hexane, having a boilingpoint of 60-68 C. and commonly known by the trademark Skellysolve B,yielding 8.1 grams of S-amino-1-methyl-3-phenylpyrazole having a meltingpoint of 124-126 C.

Although Examples A and B illustrate methods for making theS-amino-l,3-disubstituted pyrazoles necessary as one of the startingmaterials to prepare the compounds of the instant invention, suchmethods are known in the art. Furthermore, the 5-amino-1,3-disubstitutedpyrazoles are known com ounds and are therefore not deemed to be a partof this invention, except to the extent that they are starting materialsfor making the novel compounds disclosed herein.

The following examples illustrate methods of preparing various membersof the N-[4-(hydroxymethyl)-5- pyrazolylJamidine series of thisinvention.

EXAMPLE 1 1- [N- [4- (hyd roxymethyl l ,3-diphenyl--pyrazolyl]formimidoyl] pi peridine A mixture of 23.5 grams (0.1 mole) of5-amino-1,3- diphenylpyrazole and 45 grams (0.4 mole) offormylpiperidine is heated to 70 C. and to this mixture is addeddropwise 63 grams (0.41 mole) of phosphorous oxychloride with stirring.After the addition is complete, the mixture is heated to 90 C. for onehour. The mixture is then poured onto ice and stirred until the complexis hydrolyzed. A saturated solution of sodium bicarbonate is added untilthe mixture is alkaline. The crude product is filtered, washed withwater and crystallized from ethanol yielding 12.8 grams of1-[N-(4-formyl-1,3-diphenyl- 5-pyrazolyl)formimidoyl]piperidine, havinga melting point of 140-142 C.

The 1 [N-(4-formyl-1,3-diphenyl-5-pyrazoly1)formimidoyl]piperidine issuspended in methanol and cooled in an ice bath with stirring. Anequimolar proportion of sodium borohydride is added and the reactionmixture is allowed to come to room temperature and is stirred for 3 to 4hours. A precipitate forms which is filtered off. Water is added to thefiltrate until crystallization begins, and the precipitate is filteredand dried. Recrystallization from ethyl acetate yields 7.4 grams of1-[N-[4-(hydroxymethyl) 1,3 diphenyl-S-pyrazolyl]formimidoyl]piperidine,having a melting point of 170 -17l C.

Following the procedure of Example 1, the other members of this seriesof compounds may be similarly prepared. That is, the desired compound isobtained by reacting the appropriate S-amino-l,3-disubstituted pyrazolewith the corresponding formylated secondary amine and phosphorousoxychloride, and reducing the product of this reaction with a suitablereducing agent such as sodium borohydride, lithium aluminum hydride, orother known reducing agents. Table I following below lists severalspecific embodiments prepared in accordance With this procedure. ColumnsA and B describe the reactants, Column C, the product, and Column D, anidentifying physical constant, e.g., melting point in degreescentigrade.

1,3-diphenyl-5-pyrazolyl -N,N dimethylacetamidine. This intermediate isthen reduced by reaction with sodium borohydride yieldingN-[4-(hydroxymethyl) 1,3 diphenyl-S-pyrazolyl]-N,N-dimethylacetamidine,having 'a melting point of 140142 C.

Following the procedure of Example A and by using the appropriatelysubstituted halophenylhydrazine in place of phenylhydrazine, one mayprepare the 5-amino-1- halophenylpyrazoles according to the followingreaction scheme hal This material may then be used as starting materialin accordance with the procedure of Example 1 to give the 4-formylderivative which on reduction yields a halosubstituted phenyl moiety inthe 1-position of the pyrazole ring. Examples of such compounds includeTABLE I Example A B C l D,

2 5-amino-1,3 diphcnylpyrazole l-tormyl-dt-methylpipcrazinc.-1-[N-[4-(hydroxymethyl)-l.3-diphenyl-5-pyrazolyl1- 126-128tormldolj-4-rnethylpiperzainc. 3 do DlethylformtlnndeN,N-diethyl-N-[4-(hydroxymcthyl)-1,3-diphenyl-5- 152-154pyrazolylformamidine. 4 do 4-t0r1nylmorphohne4-[N-[4(hydroxymetl1yl)-1,3-diphenyl-5-pyrazolyl] 170-172 I Ifonnimidoylhormamidine. 5 5-aminc-Banethyl-l-phcnylpyraz01c.-Dlmethylformlalde N -[4-(hydroxymcthyl)-3-methyl-1-phenyl-5- 118-120 IpyrazolyllN,N-dimethyllormamidine. 6 s-amino-1-methyl-S-phenylpyrazolc.do N-[4-(hydroxymethy1)-1-methy1-3-phenyl-5- 132-133pyrazolylLN,N-dimcthyl-formamidine. 7 5-annno-1,3-d1phcny1pyrazo1e "doN-[4 (hy lroxyrncthyl)-1,3-diphenyl-5-pyrazolyl]- 149-151N,N-dimcthyllormamidine. 8 5-am1n0-1,3dimethylpyrazole oN[4-(hydroxymethyl)-1,3-dimethyl-S-pyrazolyll- 93-98 N,N-dimethyllormamidino. 9 5-am1no-l-phcnylpyrazole d0N[4-(hydroxymcthyl)-l-pl1enyl-5pymzolyl]-N,N- Oil dimethylformamirlrne.

1 The compounds shown in this column represent the final productsobtained after reduction of the intermediate formed by the reaction ofthe starting materials listed in Columns A and B.

EXAMPLE 1O N'-[4-(hydroxymethyl)-1,S-diphenyl-S-pyrazolyl] -N,N-dimethylacetamicfine Following the procedure of Example 1, 23.5 grams(0.1 mole) of S-amino-1,3-diphenylpyrazole is reacted with grams (0.4mole) of N,N-dimethylacetamide and phosphorous oxychloride.Crystallization from ethanol yields 16.8 grams ofN'-(1,3-diphenyl-5-pyrazolyl)-N,N- dimethylacetamidine. The compound isthen reacted with dimethylformamide and phosphorous oxychloride, re-

peating the same reaction scheme yielding N'-(4-formyltion. The 3 hourreading is used to calculate fever and percent reduction in feverbetween drug and placebo groups.

Table II below shows the results from a representative number of thecompounds of the instant invention. In each case, administration is bythe oral route. These doses indicated in the table are given in terms ofmilligrams per kilogram of body weight of the rat. The term LDrepresents the' dosage at which the test compound is toxic to 50 percentof the animals in the test group.

imidoyljmorpholine.

In order to demonstrate anti-inflammatory activity, a modification ofthe method described by C. A. Winter, et al., Proc. Soc. Exp. Med.,1962, 1112544 is utilized. Test compounds are administered to a group oftest rats 30 minutes prior to an injection of carrageenan into the hindpaw of the rats. Peak edema occurs 3 hours after the p'hlogisticinjection, at which time the percent inhibition is calculated from thedifference between the drug and placebo groups. The control group isadmin istered water or silane as the placebo. Administration may be bythe oral route or by injection.

Table III below shows the results for a representative number of thecompounds of this invention when tested according to this procedure. Ineach case, the compounds are administered by the oral route. The dosagesare given in terms of milligrams of compound per kilogram of animal bodyWeight. Again, the 'LD50 represents the dosage at which the testcompound is toxic to 50 percent of the animals in the test group.

TABLE III Percent Dose, iuhi- LD Compound mgJkg. bition lug/kg.

1. N-[4-(hydroxymethyl)-1,3- 30 18 6, 760

diphenyl-5-pyrazolyl]-N,N- 40 26 m h formamidine. 2B

2..." N-[4(hydroxymethyl)-1,3- 19 l,000

dimethyl-5-pyrazolyl]-N,N- dimethylformamidine.

3- N-[4-(hydroxymethyl)-1,3- 25 12 1, 000

diphenyl-5-pyrazolyl]-N,N- 50 18 dimethylacetamldine. 100 17 4.N,N-diethyl-N-[4-(hydroxy- 60 14 1,000

methyl)-1,3diphenyl-5- pyrazolylIformamidine.

5....- 4-[N-[4-(hydroxymethyl)-1,3- 50 6 81,000

diphenyl-fi-pyrazolyl] formimidoyflmorpholine.

The compounds of this invention may be administered orally, or asinjectable solutions. Oral administration includes tablet preparationsas well as oral suspensions and emulsions. Administration by injectionincludes intramuscular, intraperitoneal as well as intravenousinject-ions. Methods for formulating such preparations as tablets,emulsions, and injectable solutions are generally known in the art.

Others may practice this invention in any of the numerous ways whichwill be suggested to one skilled in the art upon reading thisdisclosure. All such practice of the invention is considered to becovered hereby provided it falls within the scope of the appended claim.

We claim:

1. A compound of the formula X CHO 1 HN=(|J-R t R Y wherein R ishydrogen or loweralkyl; R is diloweralkyl- :amino, piperidino,l-piperazinyl, 4-methyl-1-piperazinyl :and morpholino; X is phenyl orloweralkyl; and Y is phenyl, loweralkyl or halophenyl.

References Cited UNITED STATES PATENTS 3,073,851 l/1963 Steiger260-306.8 R 3,318,940 5/1967 Schmidt 260268 H 3,544,585 12/1970 Swett etal. 260-310 R JOHN D. RANDOLPH, Primary Examiner US. Cl. X.R. 1

260-2475 R, 268 K, 268 H, 293.7, 465 E; 424-248, 250, 267, 273

